Related Experiment Videos
Decrease in a constitutive form of cytochrome P-450 by macrolide antibiotics
1Division of Analytical Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Abstract:
The effects of administration of macrolide antibiotics on cytochrome P-450 in liver microsomes of male rats were investigated. The macrolides tested were those with a 14-membered ring such as oleandomycin, troleandomycin, erythromycin and erythromycin estolate, and those with a 16-membered ring such as rokitamycin, leucomycin and josamycin. Cytochrome P-450-metabolite complex was detected with oleandomycin, troleandomycin, erythromycin and erythromycin estolate, whereas no such effect was observed with rokitamycin, leucomycin and josamycin. The content of uncomplexed cytochrome P-450 in liver microsomes remained unchanged with rokitamycin, leucomycin and josamycin, decreased with troleandomycin and oleandomycin, and increased with erythromycin and erythromycin estolate, indicating that oleandomycin, troleandomycin, erythromycin and erythromycin estolate also affect the amounts of other forms of cytochrome P-450. The administration of oleandomycin, troleandomycin, erythromycin and erythromycin estolate resulted in a dramatic decrease in the activities of testosterone 2 alpha- and 16 alpha-hydroxylases in liver microsomes. Supporting these results, a marked decrease (more than 75%) in the content of P-450-male, a major constitutive form of cytochrome P-450 in male rats, was noted with oleandomycin, troleandomycin, erythromycin and erythromycin estolate, while the decrease was rather small with rokitamycin and leucomycin. We conclude that the administration of the 14-membered ring macrolides may affect drug and steroid metabolism not only by formation of P-450-metabolite complex but also by decrease in the content of P-450-male.
Insights
Fourteen-membered ring macrolide antibiotics, including erythromycin, significantly impact cytochrome P-450 (CYP450) in male rats by forming metabolite complexes and reducing CYP450-male content, affecting drug and steroid metabolism.
Area of Science:
- Pharmacology
- Biochemistry
- Toxicology
Background:
- Cytochrome P-450 (CYP450) enzymes are crucial for drug and steroid metabolism in the liver.
- Macrolide antibiotics are widely used but can interact with hepatic CYP450 systems.
- Understanding these interactions is vital for predicting drug efficacy and potential toxicity.
Purpose of the Study:
- To investigate the effects of different macrolide antibiotics on CYP450 in male rat liver microsomes.
- To differentiate the impact of 14-membered versus 16-membered ring macrolides on CYP450 activity and content.
- To elucidate the mechanisms by which macrolides influence drug and steroid metabolism.
Main Methods:
- Administration of various macrolide antibiotics (14-membered and 16-membered rings) to male rats.
- Analysis of liver microsomes for CYP450-metabolite complex formation using spectral methods.
- Quantification of uncomplexed CYP450 content and specific CYP450 isoforms (e.g., P450-male).
- Assay of testosterone hydroxylase activities as indicators of metabolic function.
Main Results:
- 14-membered ring macrolides (oleandomycin, troleandomycin, erythromycin, erythromycin estolate) formed CYP450-metabolite complexes.
- These macrolides also decreased uncomplexed CYP450 and significantly reduced P450-male content (>75%).
- Activities of testosterone 2α- and 16α-hydroxylases were markedly decreased by 14-membered ring macrolides.
- 16-membered ring macrolides (rokitamycin, leucomycin, josamycin) showed minimal effects on CYP450-metabolite complex formation and P450-male content.
Conclusions:
- 14-membered ring macrolides significantly alter hepatic CYP450 activity and content in male rats.
- The primary mechanisms involve the formation of CYP450-metabolite complexes and a substantial decrease in P450-male.
- These alterations can profoundly affect the metabolism of drugs and endogenous steroids, highlighting potential clinical implications.